Influenza is a serious public health threat, routinely killing hundreds of thousands of people worldwide each year, and millions during pandemics. Approximately 36,000 people die in the U.S. each year from influenza, primarily the elderly, young children and immune-compromised patients. The disease is caused by RNA viruses of the family Orthomyxoviridae, which includes three species that cause disease in vertebrates, including birds and mammals, such as humans. Of these three species, influenza A virus and influenza B virus are the most common disease agents in humans.
Influenza A virus is the pathogen associated with all known flu pandemics and is currently the most virulent form of the virus. A number of distinct serotypes have been isolated, including H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7. These serotypes are classified according to two viral surface proteins, hemagglutinin (H or HA) and neuroaminidase (N or NA). Within these serotypes, isolates are further characterized by a standard nomenclature specifying virus type, geographical location where first isolated, sequential number of isolation, year of isolation, and HA and NA subtype. For instance, one such isolate is A/Wisconsin/67/2005 (H3N2).
Due to the highly variable and mutable nature of influenza antigens, developing a vaccine has proven difficult. However, no reliable treatment is available for influenza, and vaccination is the most proven method for protecting against the disease and its serious complications. The vaccine must be reformulated and readministered each year in anticipation of the serotypes of the virus predicted to be prevalent in a population each flu season, and is therefore considered a “seasonal” vaccine. Typically, the most common human vaccine is a combination of two influenza A subtypes and one influenza B strain.
Despite vigorous campaigns to promote vaccination, vaccination rates in most U.S. populations remain low, far below the U.S. government's target of 60%, with higher target percentages of high risk populations, such as the target of 90% of nursing home patients. High risk populations include the elderly, children, both juvenile and infant, pregnant women and immunocompromised patients. The U.S. Centers for Disease Control reported that only 9% to 10% children with asthma received the vaccine in 2000, and less than 10% of pregnant women. (“Prevention and Control of Influenza”, Centers for Disease Control, Apr. 12, 2002.) Predictably, the rate of vaccination in less developed countries is much lower.
Presently, the most common influenza vaccines are administered by injection, these include Fluvirin®, Afluria®, FluLaval®, Fluarix®, Agrippal®, Influvac®, Mastaflu®, and Fluzone®. FluMist® is an intranasal influenza vaccine currently approved in the U.S. for use in patients between the ages of 2 and 50 years of age. For children between the ages of 2 and 8 years of age, two doses are required for vaccination, which requires two visits to a health care provider and incurs more costs. Further, no influenza vaccine is available for elderly patients that is not administered by injection. Finally, storage requirements can greatly affect both the cost and availability of influenza vaccines, as the recall of Fluvirin® in 2006 due to improper storage temperatures created shortages of the vaccine in New England.
As with most vaccines, greater immunogenicity is also sought as it correlates with greater efficacy in humans. The prior art has typically disclosed the use of recombinant proteins (e.g., U.S. Pat. Nos. 7,192,595; 6,194,546; 5,962,298), as well as the addition of adjuvants such as aluminum (U.S. Pat. No. 6,861,244) and muramyldipeptide (U.S. Pat. No. 4,826,687) to compositions to increase the immunogenicity. However, there still exists a need to develop highly effective influenza vaccines with improved storage stability and ease of administration, which are characteristics of the nanoemulsion vaccines of the present invention.
Prior teachings related to nanoemulsions are described in U.S. Pat. No. 6,015,832, which is directed to methods of inactivating Gram-positive bacteria, a bacterial spore, or Gram-negative bacteria. The methods comprise contacting the Gram-positive bacteria, bacterial spore, or Gram-negative bacteria with a bacteria-inactivating (or bacterial-spore inactivating) emulsion. U.S. Pat. No. 6,506,803 is directed to methods of killing or neutralizing microbial agents (e.g., bacterial, virus, spores, fungus, on or in humans using an emulsion. U.S. Pat. No. 6,559,189 is directed to methods for decontaminating a sample (human, animal, food, medical device, etc.) comprising contacting the sample with a nanoemulsion. The nanoemulsion, when contacted with bacteria, virus, fungi, protozoa or spores, kills or disables the pathogens. The antimicrobial nanoemulsion comprises a quaternary ammonium compound, one of ethanol/glycerol/PEG, and a surfactant. U.S. Pat. No. 6,635,676 is directed to two different compositions and methods of decontaminating samples by treating a sample with either of the compositions. Composition 1 comprises an emulsion that is antimicrobial against bacteria, virus, fungi, protozoa, and spores. The emulsions comprise an oil and a quaternary ammonium compound. U.S. Pat. No. 7,314,624 is directed to methods of inducing an immune response to an immunogen comprising treating a subject via a mucosal surface with a combination of an immunogen and a nanoemulsion. The nanoemulsion comprises oil, ethanol, a surfactant, a quaternary ammonium compound, and distilled water. US-2005-0208083-A1 and US-2006-0251684-A1 are directed to nanoemulsions having droplets with preferred sizes. US-2007-0054834-A1 is directed to compositions comprising quaternary ammonium halides and methods of using the same to treat infectious conditions. The quaternary ammonium compound may be provided as part of an emulsion. Finally, US-2007-0036831-A1 is directed to nanoemulsions comprising an anti-inflammatory agent. However, none of these references teach the methods, compositions and kits of the present invention.
In particular, U.S. Pat. No. 7,314,624 describes nanoemulsion vaccines. However, this reference does not teach the ability to induce a protective immune response to influenza with a single dose of nanoemulsion.
Thus, to increase influenza vaccination, particularly in high risk populations, there is a need for influenza vaccines that are not administered by injection for elderly patients, as well as single dose vaccines for children. The nanoemulsion composition of the present invention provides such a vaccine, which further shows improved immunogenicity and greater stability during storage.